Delayed or compromised cutaneous wound healing, particularly in diabetes, burn wounds, leg ulcers and pressure ulcers, presents significant challenges to patients and health care professional in US and worldwide. Billions of dollars spent on wound care every year, making human skin wounds a growing threat to the public health and overall economy. Hair follicle stem cell (HFSC) niches contribute to wound healing processes and Krt15 labels the hair bulge stem cell compartment. However, the mechanisms of recruitment of HFSC during wound repair and their contribution at different stages of wound healing are not well understood. Also, the factors controlling the migration of stem cells in the hair follicle compartments are not all identified. Thus, there is an unmet need to understand the role of transcription factors expressed in the different HFSC niches and regulate gene expression during cutaneous wound healing, to identify new therapeutic targets for accelerating wound healing in human patients. Transcription factor Ctip2 plays essential roles in epidermal homeostasis and barrier formation, and in cutaneous wound healing. The objective of this R15 proposal is to elucidate contributions of Ctip2+|Krt15+ stem cells to wound healing and determine the mechanistic basis for these contributions. The objective will be accomplished in the context of the central hypothesis: Ctip2 regulates expression of a gene network in HFSC compartments, and the transcriptional targets of Ctip2 within this network impact cutaneous wound healing by mobilizing stem cells and enhancing re-epithelialization and/or cellular migration. The goals of this project are to determine the contribution of Ctip2+ HFSC to cutaneous wound healing by lineage-tracing studies (Aim 1) and to identify new therapeutic targets toward accelerating wound healing by constructing Ctip2-regulated gene networks in different HFSC compartments (Aim 2). Completing this research should have: defined Ctip2-controlled genetic and regulatory networks, which directly impact wound healing; and trained students in 21st century biomedical research techniques. These studies will have implications for regenerative medicine in skin wound repair of diabetic, chronic, slow-healing wounds and will have a significant and positive impact on human health. Knowledge gained from the proposed studies may help in the healing of skin wounds in humans via restoration of the skin appendages, currently not possible.